FDA panel supports H5N1 vaccine approval

Feb 27, 2007 (CIDRAP News) – A US Food and Drug Administration (FDA) panel today recommended that the agency approve the nation's first H5N1 influenza vaccine, despite new evidence that the vaccine is less protective than reported in a clinical trial last year.

The panel of health advisors, convened to weigh the risks and benefits of the "prepandemic" vaccine made by Sanofi Pasteur, voted today to call the vaccine safe and effective, according to an Associated Press (AP) report. The FDA is not bound by the advisory panel recommendations but usually follows them.

The vaccine is based on an H5N1 virus isolated from a Vietnamese patient in 2004. Two companies, Sanofi and Chiron Corp., have been producing clade 1 H5N1 vaccines for the national stockpile under US Department of Health and Human Services (HHS) contracts worth more than $200 million.

At least 3 million courses of the vaccine are already in the national stockpile. The government's most recent pandemic planning update, released in November 2006, said up to 5 million more courses could be added in 2007 if vaccine seed stock supply and production yield are adequate. The stockpile goal is 20 million courses.

Sanofi, in a report submitted to the FDA panel, revealed that two 90-microgram (mcg) doses, administered 28 days apart, generated a protective immune response in 45% of patients. That level is less than the 54% rate reported almost a year ago in the New England Journal of Medicine. The higher rate was based on interim findings, the AP reported yesterday. The researchers used a neutralizing antibody titer of 1:40, a fourfold or more increase in antibody titer, to define adequate immune response.

The clinical trial, led by John J. Treanor, MD, was funded by the National Institute of Allergy and Infectious Diseases (NIAID) and conducted at NIAID centers at the University of Rochester in New York, the University of Maryland School of Medicine in Baltimore, and Harbor–University of California, Los Angeles, Medical Center in Los Angeles.

During discussion yesterday, panel member Monica Farley, MD, an infectious disease specialist at Emory University School of Medicine in Atlanta, said she was struggling to balance the urgency for an H5N1 vaccine with "how low to set the bar on immunogenicity," according to a Canadian Press report.

The two-dose course used in the study is 12 times the standard (15-mcg) dose used in the seasonal flu vaccine and lags behind its 75% to 90% protection rate. However, the vaccine is still better than nothing in the event of a pandemic, Norman Baylor, director of the FDA's vaccine office, told the panel, according the AP report yesterday.

In its final analysis presented to the FDA panel, Sanofi echoed interim findings that there were almost no serious side effects, even at the highest dosages. The company said no clinically significant adverse reactions were identified after a two-dose, 7-month controlled follow-up study in adults aged 18 to 64.

"The benefit of having a licensed vaccine against a potential pandemic influenza virus strain must be weighed against the risk of having no vaccine at the time of an inevitable pandemic," Baylor said, as quoted by the AP today.

Last November, the World Health Organization (WHO) cautioned governments against rushing to stockpile prepandemic flu vaccines, because too many scientific questions about them remained. The WHO said vaccines that seemed to work well against one H5N1 clade didn't work well against others. Also, the agency said no one knew what level of measured immune response indicated an adequate level of protection.

However, on Feb 16 the WHO issued a statement saying that a number of new vaccines against various strains of H5N1 look promising.

When HHS issued its most recent pandemic preparedness update, it acknowledged that a prepandemic vaccine would provide only partial protection against new viral strains. "It is, for now, the best vaccine defense we have, and so we are stockpiling it," the HHS said in the update.

The HHS has said that it is moving forward with the development of a clade 2 H5N1 vaccine based on viruses that circulated in birds in China and Indonesia in 2003-04 and spread to the Middle East, Europe, and Africa in 2005 and 2006. Also, the HHS has supported the development of cell-based vaccine production methods that would streamline and modernize vaccine production and is exploring new adjuvants that would stretch the vaccine supply.